Dr. Mariko Ishimori is strongly committed to pursuing an academic career in clinical research. She possesses a strong clinical background in rheumatology and an emerging expertise in clinical research. She now seeks to enhance her skills in the design and implementation of future studies and gain the training, experience, and support that will allow her to perform independent, investigator-initiated clinical research. She has assembled an outstanding team of mentors and collaborators including Jerome Rotter, M.D., the Director of the Division of Medical Genetics at CSMC whose major research interest is in the genetic epidemiology of common diseases; Daniel Cohn Ph.D., a senior molecular geneticist who co-directs the International Skeletal Dysplasia Registry at CSMC, and Michael Weisman, M.D., Director of the Division of Rheumatology at CSMC who is responsible for maintaining the CSMC registry of research subjects and has successfully recruited patients for major NIH-funded outcome studies in RA, OA, SLE, and AS. Together these three mentors have almost 75 years of combined experience and success in training and mentoring residents, and post-doctoral fellows towards academic careers. The K23 award objectives are to 1) further develop her skills in biostatistics, genetics, epidemiology, and research design and methodology; 2) enable her to integrate rheumatology clinical research with genetic studies; and 3) obtain guidance from co-mentors and advisors to facilitate her career development. Her specific aims are to 1) recruit a cohort of 400 probands with hand osteoarthritis (OA) and conduct careful phenotyping of disease through the use of specific, predetermined clinical and radiographic criteria; 2) determine the familiality and heritability of hand OA and specific phenotypes by analyzing study subjects affected by hand OA and their siblings; 3) identify genetic loci for hand OA in general and for different, specific, clinical and radiographic phenotypes using genome-wide association methods. Findings from this study will provide new information on the genetic mechanisms associated with hand OA and may aid our understanding of disease pathogenesis, treatment, and possibly prevention for a condition that causes disability and diminished quality of life in many people. RELEVANCE (See instructions): Hand OA is associated with substantial pain and disability, but little is understood about the underlying basis for disease despite the high prevalence in society. There are few effective therapies for symptom control and none for disease modification. This clinical genetic study may help further the understanding of hand OA pathogenesis and may lead to the development of future therapeutic or preventative interventions.